Knockdown of the AIM2 molecule attenuates ischemia-reperfusion-induced spinal neuronal pyroptosis by inhibiting AIM2 inflammasome activation and subsequent release of cleaved caspase-1 and IL-1β
Knockdown of the AIM2 molecule attenuates ischemia-reperfusion-induced spinal neuronal pyroptosis by inhibiting AIM2 inflammasome activation and subsequent release of cleaved caspase-1 and IL-1β
复制标题
AIM2 分子的敲低通过抑制 AIM2 炎性体激活和随后裂解的 caspase-1 和 IL-1beta 的释放来减轻缺血再灌注诱导的脊髓神经元焦亡。
DOI：
10.1016/j.neuropharm.2019.05.038
复制
发表时间：
2019-12-01
影响因子：
4.7
通讯作者：
Ma, Hong
中科院分区：
文献类型：
--
作者：
Li, Xiao-Qian;Yu, Qian;Ma, Hong
缺血-再灌注（IR）损伤诱导几种炎性小体的活化，这些炎性小体广泛影响神经炎症，随后影响神经元活力。黑色素瘤中缺失2（AIM 2）炎性小体在创伤性损伤后的神经元中高度表达。进行该研究以研究AIM 2分子是否作为引发剂来触发AIM 2炎性小体激活并调节小鼠IR模型中的神经元焦亡。在IR损伤后的前8小时内发生的早期运动功能障碍与在相同观察时间点血清和脑脊液（CSF）中dsDNA的大量增加密切相关。然而，随后的持续性功能障碍与随时间持续增加的包含半胱天冬酶募集结构域（ASC）、裂解的半胱天冬酶-1和IL-1 β的骨化相关斑点样蛋白的蛋白水平一致。上调的AIM 2免疫反应性主要在神经元中可见。体内si-AIM 2处理保留了部分运动功能，伴随着AIM 2、ASC、切割的半胱天冬酶-1和IL-1 β的蛋白水平降低。在体外，AIM 2分子和caspase-1之间的直接相互作用，证明了免疫荧光染色和免疫共沉淀。在这种情况下，si-AIM 2和Ac-YVAD-CMK处理均有效地维持了神经元活力，如通过具有焦亡和乳酸脱氢酶（LDH）释放的细胞百分比降低，伴随着弱免疫反应性和AIM 2-半胱天冬酶-1阳性神经元数量减少所证明的。相比之下，poly（dA-dT）处理通过逆转上述作用而加重神经元焦亡。然而，在si-Con处理后未观察到显著差异。这些结果表明，AIM 2分子通过IR诱导的异位dsDNA释放在启动AIM 2炎性小体活化中起重要作用。
Ischemia-reperfusion (IR) injury induces activation of several inflammasomes that widely affect neuroinflammation and, subsequently, neuronal viability. The absent in melanoma 2 (AIM2) inflammasome is highly expressed in neurons after traumatic injury. This study was performed to investigate whether the AIM2 molecule acts as an initiator to trigger AIM2 inflammasome activation and regulate neuronal pyroptosis in a mouse IR model. The early motor dysfunction that occurred within the first 8 h post-IR injury was closely associated with a massive increase in dsDNA in serum and cerebrospinal fluid (CSF) at the same observed timepoints. However, the subsequent persistent dysfunction was consistent with the continuously increasing protein levels of apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), cleaved caspase-1 and IL-1 beta with time. Upregulated AIM2 immunoreactivity was primarily visualized in neurons. The si-AIM2 treatment in vivo preserved part of motor function, accompanied by decreased protein levels of AIM2, ASC, cleaved caspase-1 and IL-1 beta. In vitro, the direct interactions between the AIM2 molecule and caspase-1 were demonstrated by immunofluorescence staining and coimmunoprecipitation. In this context, both si-AIM2 and Ac-YVAD-CMK treatments effectively maintained neuronal viability, as demonstrated by the decreased percentage of cells with pyroptosis and release of lactate dehydrogenase (LDH), accompanied by weak immunoreactivity and a decreased number of AIM2-caspase-1 positive neurons. By contrast, poly(dA-dT) treatment exacerbated neuronal pyroptosis by reversing the above-mentioned effects. However, no significant differences were observed after si-Con treatment. These results suggest AIM2 molecule played an important role in initiating AIM2 inflammasome activation through IR-induced release of ectopic dsDNA.